Gram-Scale Preparation of VAPOL Hydrogenphosphate: A Structurally Distinct Chiral Brønsted Acid

Abstract

A detailed gram-scale synthesis of VAPOL hydrogenphosphate, a structurally distinct chiral Brønsted acid, is presented. The reaction utilizes commercially available starting materials, proceeds with high yields and has been reproduced numerous times at scale.

VAPOL - asymmetric catalysis - Brønsted acid - ligands - phosphoric acid

References

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<A NAME="RM02110SS-16">16</A>

Commercial CHCl₃ stabilized with amylene was used; and NOT the CHCl₃ stabilized with EtOH. It was found that if the latter is used, it becomes extremely difficult to remove the residual EtOH from the product.

<A NAME="RM02110SS-17">17</A>

Sometimes it is difficult to dissolve the crude product in 35 mL of 1:1 MeOH-CHCl₃. In such cases, a little pure MeOH could be added to help the dissolution. Alternately, the mixture could be heated at ca. 30 ˚C to aid the dissolution.

<A NAME="RM02110SS-18">18</A>

The side-product was collected, subjected by rotary evaporation to dryness and high vacuum (0.1 mmHg) for 2 h. Its weight was 21 mg, and ^¹H NMR analysis showed a mixture of unidentified products.

<A NAME="RM02110SS-19">19</A>

The product, when spotted on a TLC and observed under short-wave UV (254 nm), is an intense purple spot.

<A NAME="RM02110SS-20">20</A>

Sometimes, the VAPOL hydrogenphosphate obtained after column chromatography did not dissolve in CH₂Cl₂ to give a clear solution. In such cases, the crude product should be left on high vacuum (0.1 mmHg) overnight again, which might solve the problem. If not, then the precipitation should be carried out with the emulsion obtained on the addition of CH₂Cl₂ to the crude product - it was found that it proceeded just fine even if a clear solution was not obtained.

<A NAME="RM02110SS-21">21</A>

It has been observed in some reactions^¹0 that lower asymmetric inductions are obtained if the VAPOL hydrogenphosphate is not properly dried.